2-iminobenzodiazepine derivatives

ABSTRACT

WITH A COMPOUND OF THE FORMULA Compounds of the formula   WHEREIN R1 has the same meaning as above and the respective benzene rings A and B may have one or more substituents as defined above to a ring closure reaction. Compounds of the formula II are produced by reacting a compound of the formula   WHEREIN R1 is hydrogen or alkyl and the respective benzene rings A and B may have one or more substituents which are the same or different and selected from the group consisting of halogen, nitro, trifluoromethyl, alkyl and alkoxy are prepared by subjecting a compound of the formula   WHEREIN R1 has the same meaning as defined above and R2 is hydrogen, alkyl, hydroxyalkyl or aralkyl with aminoacetonitrile. Compounds of the formula III are produced by reacting a compound of the formula

United States Patent Meguro et al.

[ Aug. 29, 197.2

[54] Z-IMINOBENZODIAZEPINE DERIVATIVES [72] Inventors: KarriiMeguro,Nishinomiya;Yutaka Kuwada, Ashiya, Hyogo; Toru Masuda,Nishinomiya, all of Japan [73] Assignee: Takeda Chemical Industries,Ltd.,

Higashi-ku, Osaka, Japan [22] Filed: July 8, 1969 211 Appl. No.: 840,032

[30] Foreign Application Priority Data July 12, 1968 Japan ..43/49236July 12, 1968 I Japan ..43/49237 July 8, 1968 Japan ..43/4'[66l June 21,1969 Japan .Q ..44/49l78 US. Cl. ..260/239 BD, 260/239.3 D, 260/465 E,

[51] Int. Cl...C07c 119/14, CO7c l2l/66,CO7d 53/06 v [58] Field ofSearch ..260/239 BD [5 6] References Cited UNITED STATES PATENTS3,177,201 4/1965 Reeder et a1. ..260/239 OTHER PUBLICATIONSl-louben-Weyl, Methoden der Organischen Chemie, Vol. 11/2, (Stuttgart,1958), pp. 39- 51. QD258H7.

Elderfield, Heterocyclic Compounds, Vol. 9, (New York, 196 pp. 337 341.QD40OE4.

Smith, Open- Chain Nitrogen Compounds, Vol. 1, (New York, 1965), page179. OD 412. N156.

Primary Examiner-Alton D. Rollins Attorney-Wenderoth, Lind & Ponack [57]ABSTRACT Compounds of the formula wherein R is hydrogen or alkyl and therespective benzene rings A and B may have one or more substituents whichare the same or different and selected from the group consisting ofhalogen, nitro, trifluoromethyl, alkyl and alkoxy are prepared bysubjecting a compound of the formula wherein R, has the same meaning asabove and the respective benzene rings A and B may have one or moresubstituents as defined above to a ring closure reaction. Compounds ofthe formula II are produced by reacting a compound of the formula (III)wherein R, has the same meaning as defined above and R is hydrogen,alkyl, hydroxyalkyl or aralkyl with aminoacetonitrile. Compounds of theformula IH are produced by reacting a compound of the formula NHRr B l A7 V a compound of the formula R NH wherein R is hydrogen, alkyl,hydroxyalkyl or aralkyl.

tranquilizing, muscle relaxant, anticonvulsant agents. Compounds of theformula wherein R, is hydrogen, or alkyl and the respective benzenerings A and B may have one or more substituents which are the same ordifferent and selected from the group consisting of halogen, nitro,trifluoromethyl, lower alkyl and lower alkoxy, are useful in thepreparation of compounds II.

6 Claims, No Drawings 2-IMINOBENZODIAZEPINE DERIVATIVESThe2-iminobenzodiazepine derivatives (1) wherein R is hydrogen have beenknown as useful as tranquil- This invention relates to benzodiazepinederivatives lizers. For the production of the benzodiazepine derivaofthe general formula tives (I) wherein R is hydrogen, the followingmethod 5 has-been proposed:

1. allowing an aminobenzophenone derivative of the general formulawherein R is hydrogen. or alkyl and the respective. benzene rings A andB may have one or more substituents which are the same or different andare selected from the group consisting of halogen, nitro,trifluoromethyl, alkyl and alkoxy. The present invention also relates toa process for the production of the 2iminobenzodiazepine derivatives(1).

wherein R, for example, is hydrogen or chlorine, to react withhydroxylamine, whereby the corresponding aminobenzophenone oximeRegarding the above formula (I), when the symbol NHz R is an alkylgroup, the compounds are represented by the general formula -C=NOH isproduced, 2. reacting the resulting aminobezophenone oxime withchloroacetylchloride, whereby 2-chloromethyl-4-phenylquinazoline-S-oxide and, when the symbol R is hydrogen atom, theyare N represented by the general formula r l NH:

Q) is yielded,

H 3. subjecting the resulting oxide to a ring expansion The compound (Imay form also an lsomer of the reaction with ammonia, whereby2-arnino-5-phenyl-3 formula H-l,4-benzodiazepine 4-oxide 5 is yielded,and finally Hereinafter, the compounds of the formula (I) are 4.treating the resulting oxide with deoxygenating simply referred to as2-iminobenzodiazepine derivaagent, e.g. phosphorus trichloride, whereby2-amino-5- tives. phenyl-3H-l,4-benzodiazepine is given.

As seen from the above,-the known method involves many complicatedsteps, and the yield of the final product is very low, e.g. aroundpercent overall. Thus, the known method is hardly practicable from anindustrial point of view.

Moreover, the known method can be applied only for the production of2-iminobenzodiazepine derivatives (I) wherein R is H, and the 2-iminobenzodiazepine derivatives (I) wherein R is other than hydrogen (e.g. alkyl) cannot be produced by the known method. In fact, the1-alkyl-2- iminobenzodiazepine derivatives (R of the formula (I) isalkyl) have never been produced, so far as the present inventors areaware. The present inventors have made extensive studies for finding outa process for producing 2-iminobenzodiazepine derivatives (I), which isindustrially practicable and can be applied also for the production oflalkyl-2-iminobenzodiazepine derivatives. The present invention is theculmination of the studies.

' The principal object of the present invention is to provide anindustrially practicable process for producing Z-iminobenzodiazepinederivatives (I).

Another object of the present invention is to provide novel and usefull-alkyl-2-iminobenzodiazepine derivatives. Still another object of thepresent invention is to provide a method for the production of novel 1-alkyl-2-iminobenzodiazepine derivatives.

The process of the present invention comprises subjecting compounds ofthe general formula wherein R has the same meaning as above and therespective benzene rings A and B may have one or more substituents asdefined above to a ring closure reaction. The starting compounds of theformula (II) are novel compounds and can prepared by a method whichcomprises allowing compounds of the general formula NHR (III) compoundof the general formula wherein R and R have the same meaning as definedabove and the respective benzene rings A and B may have one or moresubstituents as defined above and allowing the resulting compounds (V)to react with aminoacetonitrile.

By using the method of the present invention, the object2-iminobenzodiazepine derivatives of the formula (I) can easily beprepared in much higher yield, e.g. not lower than about 50 percent andin most cases more than percent through a smaller number of steps thanthe known method starting from the same aminobenzophenone derivative asin the known method, ad therefore the present method is muchadvantageous from a viewpoint of industrial practicability.

Furthermore, according to the present method, it is possible to producelalkyl-2-iminobenzodiazepine derivatives, i.e. compounds of the formula(I) wherein R is alkyl, which are novel compounds and have never beenproduced by known methods. The thus producedl-alkyl-2-iminobenzodiazepine derivatives have much highermuscle-relaxant, anticonvulsant, taming and sedative effect thanZ-iminobenzodiazepine derivatives i.e. compounds of the formula (I)wherein R is hydrogen.

Referring to the afore-mentioned formulas, as the alkyl represented by Rlower alkyls and cycloalkyls having up to six carbon atoms arepreferable. These may be exemplified by methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, tert-butyl, amyl, hexyl, cyclopentyl,cyclohexyl, etc. Among the lower alkyls, methyl and ethyl groups aremost desirable. The respective benzene rings A and B may have one ormore substituents which are the same or different and are selected fromthe group consisting of halogen, nitro, trifluoromethyl, alkyl andalkoxy at optional position(s).

The halogen which may be attached to the benzene rings A and/or B ischlorine, bromine, iodine, and fluorine. The alkyl, which may beattached to the benzene rings A and/or B is exemplified by lower alkyl,e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and the like.The alkoxy which may be attached to the benzene rings A and/or B isexemplified by lower alkoxy, for example, methoxy, ethoxy, propoxy,butoxy, and the like.

In the compounds of formulas (IV) and (V), which are used for theproduction of the starting materials (ll) of the present method, thealkyl represented by R may be straight, branched or cyclic ones whichare exemplified by lower alkyls having'one to six carbon atoms such asmethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, hexyl,cyclohexyl, cyclopentyl, etc., the hydroxyalkyl represented by the R isexemplified by lower hydroxyalkyls having two to four carbon atoms e.g.hydroxyethyl, hydroxypropyl, hydroxybutyl, etc. and the aralkylrepresented by the R is exemplified by benzyl, phenethyl, etc;

Hereinafter, the method of the present invention is described in detailincluding the steps of the production of the compounds (II), which arethe starting materials of this method, from the compounds (III) throughthe compounds (V). The reaction between the aminobenzophenonederivatives (III) and the primary amines (IV). is conducted underheating in the presence or the absence of a solvent. The heatingtemperature is generally about 120 C. to about 130 C. An amount oftheamines (IV) relative to the compounds ([11) is generally not lowerthan 1 mole and preferably about 5 to about moles per mole of thecompounds (III). The compound (III) and/or the amine (IV) may be used inthe form of their acid salts (e.g. hydrochloride, sulfate, etc.).

It is recommended that the reaction be carried out in the presence of,as a catalyst, Z-methylirnidazole or its mineral acid salts (e. g.hydrochloride, sulfate, etc.

The amount of the catalyst is generally not lower than one mole andpreferably about 1 to about 5 moles per mole of the compounds (III).

Then, the compounds of the formula (V) produced in the above step areallowed to react with aminoacetonitrile, wherebya-phenylbenzylidenearninoacetonitrile derivatives (H) are producedalmost quantitatively.

The reaction is generally carried out in the presence of anhydroussolvent. The preferable solvents are polar ones such as methanol,ethanol, pyridine, dimethylformamide, acetonitrile, etc.

The aminoacetonitrile is usually employed in the form of its acid salts,(e.g. hydrochloride, sulfate, hydrogen sulfate, etc.), and it ispreferable to carry out the reaction in the presence of deacidifyingagents such as triethylamine, pyridine, N-methylpiperidine, N-ethylpiperidine and 2-methylimidazole, etc.

The reaction is carried out generally near the boiling point of thesolvent used, but, is required, may be carried out at higher or lowertemperatures.

The amount of aminoacetonitrile employed is generally not lower than 1mole, practically about 2 moles to 5 moles, per mole of the compounds(V).

The a-phenylbenzylidene aminoacetonitrile derivatives (II) thus producedare novel compounds and are used as the starting materials for thepresent method.

The a-phenylbenzylideneaminoacetonitrile derivatives (11) thus producedcan be isolated in a conventional manner, for example, by distilling thesolvent from the reaction mixture and extracting the residue with asuitable solvent and finally evaporating the solvent. But, the reactionmixture per se may be used as the starting substance for the presentmethod.

The compound (II) and the compound (V) may form two isomers, one beingsyn-form and the other being anti-form, and therefore, those compoundsmay be obtained as a mixture of the two isomers. The mixture of twoisomers may be separated into individual isomers after per se knownmanner, for instance, fractional crystallization of the mixture.However, in the method of the present invention and also in theproduction of the starting material for the present method, it ismeaningless to separate these two isomers from the industrial viewpoint, because each of the compounds (II) and (V) can be used in thenext step, irrespective of its form. But, of course, any of theseparated isomers, i.e. anti-form or syn-form may be used for theintermediate.

In the method of the present invention, thea-phenylbenzylideneaminoacetonitrile derivatives (II) are subjectedto aring-closure reaction. Generally the ringclosure reaction can easilyproceed by keeping the compound (II) in a solvent in the presence of anacid or an alkali as a catalyst. The acid employable in the ringclosurereaction may be such inorganic acids, e.g. hydrochloric acid, sulfuricacid, phosphoric acid, etc., and organic acids, e. g. aliphaticcarboxylic acid such as acetic acid, propioni acid, trifluoroaceticacid, and organic sulfonic acid such as benzene sulfonic acid,ptoluenesulfonic acid.

The alkali employable may be exemplified by alkali hydroxides such assodium hydroxide and potassium hydroxide.

Among the acids and alkalis, the acids are more 7 preferable. Among theacids, strong acids are preferable and the use is most desirably made ofinorganic acid, especially hydrochloric acid. The amount of the acidemployed is generally in excess, practically not lower than 2 moles, andpreferably around 20 moles per mole of thea-phenylbenzylideneaminoacetonitriles (II).

The amount of the alkali employed is not lower than about 1 mole, andpractically about 1 mole per mole of thea-phenylbenzylidenaminoacetonitriles (II).

The solvent usable is exemplified by an lower alcohol (e.g. methanol,ethanol, propanol, butanol, etc.) and aliphatic carboxylic acid (e.g.acetic acid, propionic acid, etc.).

The reaction temperature is about 0 C. to about 30- C., but, ifrequired, may be at higher or lower temperatures.

The benzodiazepine derivatives (I) thus produced can be isolated in theform of free bases or suitable acid salts (e.g. hydrochloride, sulfate,acetate, etc.) by per se conventional means, for example, by distillingthe solvent from the reaction mixture, extracting the residue with asuitable solvent and finally evaporating the solvent. For purposes ofthis invention the salts of the free bases are the full equivalentsthereof.

Among the benzodiazepine derivatives (I), l-alkyl-2- iminobenzodiazepinederivatives, i.e. the compounds (I) wherein R is alkyl, are novelcompounds and show much higher muscle-relaxant, anticonvulsant, sedativeand taming effect than the known benzodiazepine derivatives, i.e. thecompounds (I) wherein R, is hydrogen, and therefore they can be used astranquillizing, muscle-relaxant and anticonvulsant agents, and the like,most advantageously. The benzodiazepine derivatives (I) as well as theiracid salts are orally or parenterally administered per se or in asuitable form such as powder, granule, tablet or injection solutionadmixed with a pharmaceutically acceptable carrier or adjuvant. Dose ofthe benzodiazepine derivatives (I) to be administered varies with therespective compounds, but generally falls within a range of from about 1to about 30 milligrams upon oral administration, and about 0.5 to about10 milligrams upon parenteral administration for human adult per day.

Further, the benzodiazepine derivatives (1) produced by the presentmethod may be converted into known benzodiazepin-2-one derivatives,which are also useful as tranquillizing, muscle relaxant, anticonvulsantand sleep inducing agents by alcoholysis or hydrolysis.

For further detailed explanation of the invention, the followingexamples are given, wherein the term part(s) means weight part(s) unlessotherwise noted, and the relationship between part(s)" and part(s) byvolume corresponds to that between gram(s) and milliliter(s).

EXAMPLE PARTS [-1 Production of the Starting Material The step ofEXAMPLE 1 A mixture of 2.3 parts of 2-amino-5- chlorobenzophenone, 6.1parts by volume of monoethanolamine and 1.2 parts of 2-methylimidazolehydrochloride is heated at 125 to 130 C. for 2 hours. After cooling, 200parts of water is added to the resulting mixture, whereby2-amino-5-chloro-a-phenylbenzylideneaminoethanol is precipitated as paleyellow crystals. Melting point: 122 to 125 C. Yield: 2.6 parts (95percent). Thus obtained crystals per se are employable as the startingmaterial for the subsequent reaction without further purification.

For the purpose of more precise identification of the crystals, a smallamount of the crystals is, after recrystallization from a mixture ofbenzene and hexane, subjected to determination of melting point and toelementary analysis, whereby the following result is obtained.

Melting point: 125C to 126C. Elementary analysis:

Calculated for C,,,H,5C1N,O

C 65.57, H 5.50, N 10.20 Found: C 65.32, H 5.47, N 10.14

EXAMPLE2 A mixture of 2.4 parts of 2-amino-5- nitrobenzophenone, 6.1parts by volume of monoethanolamine and 1.2 parts of 2-methy1imidazolehydrochloride is heated at 120 C. for 2 hours. After cooling, theresulting reaction mixture is added to 50 parts by volume of water,whereby 2-amino-5-nitro-aphenyl-benzylideneaminoethanol is precipitatedas crystals. Thus obtained crystals per se are employable as thestarting material for the subsequent process without furtherpurification. Yield: 2.7 parts (96 percent).

For the purpose of identification, a small amount of the crystals is,after subjected to determination of the melting point and to elementaryanalysis, recrystallized from benzene. Melting point: 151 to 152 C.(yellow needles).

Elementary analysis:

Calculated for C H N O C: 63.15, H: 5.30, N: 14.73 Found C: 62.94, H:5.08, N: 14.56

EXAMPLE 3 A mixture of 30 parts chlorobenzophenone, 150 partscyclohexylamine and 60 parts of 2-methylimidazole hydrochloride isheated at a temperature ranging from to C. for 9 hours. After cooling,the resulting mixture is added to 300 parts by volume of water, followedby extraction with ethyl acetate. From the ethyl acetate extract thesolvent is distilled off, whereby 2-amino-5-chloro-a-phenylbenzylideneaminocyclohexane is obtainedquantitatively. The product per se can be used as the starting materialfor the subsequent process without further purification.

For the purpose of identification, a small amount of the product isrecrystallized from n-hexane to give 2-amino-5chloro-oz-phenylbenzylideneaminocyclohexane as colorless flakesmelting at 136 to 138 C., which corresponds to one of the two isomers.

of 2-amino-5- Elementary analysis:

Calculated for C,,H,,C1N,

C: 72.94, H: 6.77, N: 8.96 Found C: 72.92, H: 6.60, N: 8.72.

EXAMPLE 4 A mixture of 2.4 parts of 2-amino-5- nitrobenzophenone, 12parts by volume of cyclohexylarnine and 3.6 parts of 2-methylimidazolehydrochloride is heated at 130 C. for 7 hours. After cooling, theresulting mixture is added to 50 parts by volume of water, whereby2-amino-5-nitro-a-phenylbenzylideneaminocyclohexane is percipitated ascrystals. Yield: 3 parts (94 percent). Melting point: 131 to 137 C. Thusobtained crystals per se are employable as the starting material for thesubsequent process without further purification. For the purpose of moreprecise identification, a small amount of the crystals is recrystallizedfrom methanol to give yellow needles melting at 158 to 159 C., whichcorresponds to one of the two isomers.

Elementary analysis:

Calculated for c H mo,

C: 70.56, H: 6.55, N: 13.00 Found C: 70.32, H: 6.58, N: 12.87

EXAMPLE 5 A mixture of 4.6 parts of 2-amino-5- chlorobenzophenone, 40parts by volume of n-butylamine and 7.2 parts of 2-methylimidazolehydrochloride is heated in a sealed vessel at a temperature ranging from130 to 140 C. for 4 hours. The butylamine is distilled off under reducedpressure. The

by volume of resulting residue is partitioned between 200 parts byvolume of water and 200 parts by volume of ethyl acetate. The ethylacetate layer is washed with water and dried over sodium sulfate,followed by distillation of the solvent. This procedure givesl-(2-amino-5- chloro-a-phenylbenzylideneamino) butane quantitatively asa yellow oily substance. Thus obtained oily substance per se isemployable as the starting material for the subsequent process withoutfurther purification.

The oily substance is confirmed to be a mixture of anti and syn-forms bythin layer chromatography, infrared absorption spectrum and nuclearmagnetic resonance spectrum.

EXAMPLE 6 A mixture of 4.8 parts of 2-amino-5- nitrobenzophenone, 40parts by volume of n-butylamine and 7.2 parts of 2-methylimidazolehydrochloride is heated at 130 C. in a sealed vessel for 6 hours. Thebutylamine is distilled off under reduced pressure, followed by additionof 200 parts by volume of water. Thus separated oil is extracted withethyl acetate, followed by distillation of the ethyl acetate, whereby1-(2-aminor5-nitro-a-phenylbenzylideneamino)butane is obtained as ayellow oily substance. Yield: 5.9 parts (99 percent). Thus obtained oilysubstance per se is employable as the starting material for thesubsequent process without further purification.

The oily substance is confirmed to be a mixture of syn and anti-forms bythin layer chromatography, infrared absorption spectrum and nuclearmagnetic resonance spectrum.

EXAMPLE 7 A mixture of 10 parts of 2-methylamino-5- chlorobenzophenone,25 parts of monoethanolamine and 4.8 parts of 2-methylimidazolehydrochloride is heated at 130 C. for 2 hours. After cooling, 100 partsof water is added to the resulting mixture. The aqueous mixture isextracted with ethyl acetate, followed by distillation of the solvent,whereby 2-methylamino-5- chloro-a-phenylbenzylideneaminoethanol isobtained.

' lization is added a small amount of water and the mixture is leftstanding, whereby the other isomer is given. 1

Yield: 11 parts (96 percent). Thus obtained product per se is employableas the starting material for the subsequent process without fuitherpurification.

For the purpose of identification, a small amount of the product isrecrystallized from n-hexane to give yellow pillars melting at 98 to 99C.

Elementary analysis:

Calculated for C,,H,,N,0C1

C: 66.54, H: 5.93, N: 9.70 Found C: 66.65, H: 5.82, N: 9.48

EXAMPLE 8 For the purpose of identification, a small amount of thecrystals is recrystallized from a mixture of benzene and hexane to givecolorless crystals melting at 1 10 C.

Elementary analysis:

Calculated for C, H,,N O C: 74.97, H: 6.71, N: 11.66 Found: C: 75.00, H:6.72, N: 11.39

The crystals are a mixture of a synand anti-forms and, when subjectedrepeatedly to a fractional crystallization,- the mixture is separatedinto individual isomers, i.e. one being colorless needles melting at atemperature ranging from 1 18 to 1 19 C. and the other being colorlessflakes melting at 1 165 C. Elementary analysis of each of the isomerscoincides with the calcu lated value.

EXAMPLE 9 A mixture of 2.4 parts of 2-methylamino-5- chlorobenzophenone,10 parts of c'yclohexylamine and 4.8 parts of 2- methylimidazole.hydrochloride is heated at to C. for 7 hours. After cooling, 100 partsof water is added to the resulting mixture, followed by extraction withethyl acetate. The ethyl acetate is distilled off to give quantitatively2-methylamino-5- chloro-a-phenylbenzylideneaminocyclohexane as anElementary analysis:

Calculated for C,,H,,C|N,

C: 73.49, H: 7.09, N: 8.57 Found: C: 73.53, H: 7.20, N: 8.77

To the mother liquor obtained in the above recrystal- The product isrecrystallized from ethanol to give colorless granules melting at atemperature ranging from 10l.5 to 102.5 C.

Elementary analysis:

Calculated for c l-l ClN C: 73.49, H: 7.09, N: 8.57 Found: C: 73.27, H:7.15, N: 8.74

EXAMPLE 10 A mixture of 4.6 parts of 2-amino-5- chlorobenzophenone, 7parts of n-propanolamine and 2.4 parts of 2-methylimidazolehydrochloride is heated at 180 C. for 30 minutes. To the resultingmixture is added 10 parts of water, followed by extraction withmethylenechloride. The solvent is distilled off to give quantitatively2-amino-5-chloro-a-phenylbenzylideneaminopropan-3-ol. Thus obtainedproduct per se is employable as the starting material for the subsequentprocess without further purification.

For the purpose of identification, a small amount of the product istreated with n-hexane to give crystals melting at 102 to 105 C., whichcorresponds to one of the two isomers.

Elementary analysis:

Calculated for C,,H,.,C1N,O

C: 66.53, H: 5.93, N: 9.70 Found: C: 66.52, H: 5.97, N: 9.65

EXAMPLE 11 To 100 parts of volume of methanol is added 10 parts ofconcentrated sulfuric acid, followed by addition of 16.4 parts of2-methylimidazole. The mixture is concentrated under reduced pressure togive 2- methylimidazole sulfate. To the residue are added 42.3 parts of2-amino-5-methylbenzophenone and 122 parts of monoethanolamine, followedby heating at 130 C. for 3.5 hours. After cooling, the mixture is pouredinto 1,000 parts of ice-water, followed by extraction with chloroform.The chloroform extract is dried over sodium sulfate, followed bydistillation of the solvent. The residue is treated with petroleum etherto give 2-amino- 5-methyl-a-phenylbenzylideneaminoethanol as pale yellowcrystals. Yield: 40 parts (80 percent). Thus obtained crystals per seare employable as the starting material for the subsequent processwithout further purification.

For the purpose of identification, a small amount of the crystals isrecrystallized from a mixture of benzene and n-hexane to give colorlessprisms melting at 72 to 73 C.

Elementary analysis:

Calculated for c u mo C: 75.66, H: 7.13, N: 11.02 Found: C: 75.73, H:7.08, N: 11.08

EXAMPLE 12 A homogeneous mixture of 9.1 parts 2-amino-5-methoxybenzophenone, 49 parts of monoethanolamine and 105 parts of2-methylimidazole sulfate is heated at 130 C. for 2.5 hours. Aftercooling, the mixture is added to 500 parts of cold water, followed byextraction with ethyl ether. The ethyl ether extract is washed withwater and dried over sodium sulfate, followed by distillation of thesolvent under reduced pressure. This procedure gives quantitatively2-amino-5-methoxy-aphenylbenzylideneaminoethanol as an oily substance.Thus obtained oily substance per se is employable as the startingmaterial for the subsequent process without further purification.

EXAMPLE 13 To 100 parts by volume of methanol is added 5.9 parts ofconcentrated sulfuric acid, followed by adding gradually 9.8 parts of2-methylimidazole. The mixture is concentrated under reduced pressure todryness. To the residue are added 15 parts of 2-amino-5-trifluoromethylbenzophenone and parts by volume of monoethanolamine, andthe mixture is heated at 130 C. for 2 hours. After cooling, the mixtureis poured into 200 parts of cold water, followed by extraction withcarbon tetrachloride. The carbon terachloride extract is washedthoroughly with water and dried over sodium sulfate, followed bydistillation of the solvent. This procedure yields 2-amino-5-trifluoromethyl-a-phenylbenzylideneaminoethanol as a reddish yellow oilysubstance almost quantitatively. Thus obtained oily substance per se isemployable as the starting material for the subsequent process withoutfurther purification.

EXAMPLE-PART I-2 Production of the Starting Material The step of C=NR1 II G] EXAMPLE 14 To a solution of 5.5 parts of the crystals prepared inExample 1 (2-amino-5-chloro-a-phenylbenzylideneaminoethanol) and 9.8parts of 2- methylimidazole in 150 partsby volume of methanol, 9.2 partsof aminoacetonitrile hydrogen sulfate is added, and the mixture isrefluxed for 1 hour, followed by distillation of the solvent. To theresidue is added parts by volume of water, and the mixture is extractedwith ethyl acetate. The ethyl acetate layer is washed well with waterand dried over sodium sulfate, followed by distillation of the solvent.The procedure gives2-amino-5-chloro-a-phenylbenzylideneaminoacetonitrile as a yellow oilysubstance in quantitative 'yield. Thus obtained product per se isemployable as the starting material for the subsequent process withoutfurther purification.

For the purpose of identification, a small amount of the product isrecrystallized from isopropyl ether to give crystals. Recrystallizationfrom isopropyl ether yields yellow prisms melting at to 1 12 C., whichcorrespond to one of the two isomers.

Elementary analysis:

Calculated for C J'i CIN C: 66.79, H: 4.48, N: 15.58 Found: C: 66.54, H:4.50, N: 15.47

EXAMPLE 15 To a solution of 8.4 parts of the oil prepared in Example 7(2-methylamino-5-chloro-a-phenylbenzylideneaminoethanol) and 14.7 partsof 2- methylimidazole in parts by volume of ethanol, 13.8 parts ofaminoacetonitrile hydrogen sulfate is added. The mixture is refluxed for30 minutes, followed by distillation of the solvent. To the residue isadded water and the aqueous mixture is extracted with ethyl acetate. Theethyl acetate layer is washed with water, and dried over sodium sulfate,followed by distillation of the solvent, whereby 8.2 parts of2-methylamino-5- chloro-a-phenylbenzylideneaminoacetonitrile is obtainedas a yellow oily substance. Yield 99 percent. Thus obtained oilysubstance per se is employable as the starting material for thesubsequent process without further purification.

For the purpose of identification, a small amount of the product iscrystallized from methanol to give yellow flakes melting at 127 to 128C.

Elementary analysis:

Calculated for C H CIN,

C: 67.72, H: 4.97, N: 14.81 Found: C: 67.78, H: 4.91, N: 14.73

These flakes correspond to anti-form. When the mother liquor isconcentrated and allowed to stand, colorless needles are obtained.Melting point: 103 to 104 C.

Elementary analysis:

Calculated for C H CIN;

C: 67.72, H: 4.97, N: 14.81 Found: C: 67.72, H: 4.93, N: 14.88

These needles correspond to syn-form.

EXAMPLE 16 To a solution of 14.3 parts of the crystals prepared inExample 2 (2-amino-5-nitro-a-phenylbenzylideneaminoethanol) and 24.6parts of 2- methylimidazole in 400 parts by volume of ethanol, 23.1parts of aminoacetonitrile hydrogen sulfate is added. The mixture isrefluxed for 1 hour, followed by distillation of the solvent. To theresidue is added 500 parts by volume of water, and the mixture issubjected to extraction with ethyl acetate. The ethyl acetate layer iswashed with water and dried over sodium sulfate, followed bydistillation of the solvent, whereby 2-amino--nitro-a-phenylbenzylideneaminoacetonitrile is obtained as a red oilysubstance in quantitative yield. Thus obtained product per se isemployable as the starting material for the subsequent process withoutfurther purification.

For the purpose of identification, a small amount of methanol is addedto a small amount of the above oil, whereby yellow crystals areseparated out. Recrystallization from ethanol yields yellow prisms.Melting point: 154 to 155 C.

Elementary analysis:

Calculated for C, H,,N,0,

C: 64.27, H: 4.32, N: 19.99 Found: C: 64.56, H: 4.54, N: 19.95

These prisms correspond to one of the two isomers.

EXAMPLE 17 To a solution of 1.3 part of the oil prepared in Example 3(2-amino-5-chloro-a-phenylbenzylideneaminocyclohexane) and 1.6 part of2-methylimidazole in 40 parts by volume of methanol, 1.5 part 'of2-methylimidaz0le and 4.6 parts of aminoacetonitrile hydrogen sulfate.The mixture is refluxed for 1 hour, followed by distillation of thesolvent. The residue is treated in the same manner as Example 16 to give2- amino-5-nitro-a-phenylbenzylideneaminoacetonitrile as a red oilysubstance in quantitative yield. Thus obtained oily-substance per se isemployable as the starting material for the subsequent process withoutfurther purification.

For the purpose of identification, a small amount of the product isrecrystallized from toluene to give yellowish-red crystals of one of theisomers. The melting point and infrared absorption spectrum of theproduct are identical with those of the end product of Example bl6.

EXAMPLE 19 ble as the starting material for the subsequent processaminoacetonitrile hydrogen sulfate is added, and the resulting mixtureis refluxed for 4.5 hours, followed by distillation of the solvent.Using ethyl acetate, the residue is treated in the same manner asExample 14, whereby2-amino-5-chloro-a-phenylbenzylideneaminoacetonitrile is obtained as ayellow oily substance in quantitative yield. Thus obtained product perse is employable as the starting material for the subsequent processwithout further purification.

For the purpose of analysis, a small amount of the product isrecrystallized from di-isopropyl ether in the same manner as Example 14to yield yellow prisms of one of the isomers. The melting point andinfrared absorption spectrum of this product are identical with those ofthe end product of Example 14.

EXAMPLE 18 in 10 parts by volume of methanol are dissolved 2.4 parts of2-amino-5-nitrobenzophenonimine, 5 parts of without furtherpurification.

EXAMPLE 20 In a solution of 68.5 parts of aminoacetonitrile hydrogensulfate and 74 parts of 2-methylimidazole in 700 parts by volume ofmethanol is dissolved 382 parts of the crystals prepared in Example 11(2-amino-5- methyl-a-phenylbenzylidenearninoethanol). The mixture isrefluxed for 20 minutes and the methanol is distilled off under reducedpressure. To the residue is added water, followed by extraction withethyl acetate. The ethyl acetate layer is washed well with water anddried over sodium sulfate, followed by distillation of the solvent underreduced pressure. The procedure yields2-amino-5-methyl-a-phenylbenzylideneaminoacetonitrile as an oilysubstance quantitatively. The oil per se is employable as the startingmaterial for the subsequent process without further purification.

EXAMPLE 21 To a solution of 20 parts of -the oily substance prepared inExample 13 (2-amino-5-trifluoromethyl-aphenylbenzylideneaminoethanol) in350 parts of volume of methanol are added 28 parts of 2- methylimidazoleand 26.3 parts of aminoacetonitrile hydrogen sulfate. The mixture isrefluxed for 1 hour, followed by distillation of the methanol. To theresidue is added water, followed by extractions with ethyl ether. Theethyl ether layer is washed with water, dried over sodium sulfate,followed by distillation of the ethyl ether. The procedure yields2-arnino-5-trifluoromethyla-phenylbenzylideneaminoacetonitrile as anoily substance almost quantitatively. Thus obtained oily substance perse is employable as the starting material for the subsequent processwithout further purification.

EXAMPLE 22 A solution of 1.35 parts of the oily substance prepared inExample 12 (2-amino-5-methoxy-a-phenylbenzylideneaminoethanol), 2.3parts of aminoacetonitrile hydrogen sulfate and 2.46 parts of 2-methylimidazole in 10 parts by volume of methanol is refluxed forminutes, followed by distillation of the solvent. To the residue isadded 50 parts by volume of water and the mixture is extracted withchloroform. The chloroform extract is washed with water and dried oversodium sulfate, followed by distillation of the solvent. The procedureyields 2-amino-5-methoxy-aphenylbenzylideneaminoacetonitrile as an oilysubstance quantitatively. Thus obtained oil per se is employable as thestarting material for the subsequent process without furtherpurification.

EXAMPLE-PART II Production of the Object Material The step of NHR1 A lEXAMPLE 23 Elementary analysis:

Calculated for C,,,H,,C1N;,

C: 66.79, H: 4.48, N: 15.58 Found: C: 66.77, H: 4.06, N: 15.53

EXAMPLE 24 To a solution of 270 parts of the oily substance prepared inExample 14 (2-amino-5-chloro-a-phenylbenzylideneaminoacetonitrile) in 6parts by volume of ethanol is added 1 part by volume of 1 N KOH solutionin ethanol. The mixture is allowed to stand overnight at roomtemperature. The ethanol is distilled off at about 40 C. under reducedpressure. The residue is extracted with ethyl acetate, and the ethylacetate extract is washed with water and dried over sodium sulfate.After the solvent is distilled off, the residue is recrystallized frommethanol. The procedure gives 2-amino-7-chloro-5-phenyl-3l-l-1,4-benzodiazepine. Yield: percent. The melting point andelementary analysis of this product are identical with those of the endproduct of Example 23.

EXAMPLE 25 A solution of 2.3 parts of the oily substance prepared inExample 19 (2-amino-a-phenylbenzylideneaminoacetonitrile) in 25 parts byvolume of methanol is saturated with dry hydrogen chloride gas undercooling with ice, and the solution is allowed to stand for 1 hour. Thesolution is concentrated to a half of the initial volume under reducedpressure and at a temperature of 30 C. or below. The concentrate ispoured into 15 percent aqueous ammonia solution and the resultingcrystals are colled by filtration. The procedure gives2-amino-5-phenyl-3H-l ,4- benzodiazepine. Recrystallization from acetonegives colorless needles melting at 217 to 218 C. (decomposition). Yield;70 percent.

Elementary analysis:

Calculated for C H N C: 76.57, H: 5.57, N: 17.86 Found: C: 76.47, H:5.55, N: 17.79

EXAMPLE 26 A solution of 2.8 parts of the oily substance prepared inExample 16 (2-amino-5-nitro-a-phenylbenzylidenearninoacetonitrile) in 30parts by volume of ethanol is saturated with dry hydrogen chloride gasunder cooling with ice. After 1 hour, the resulting crystals arecollected by filtration and washed with acetone. The procedure gives2-amino-7-nitro-5-pheny1-3H-1,4-benzodiazepine dihydrochloride meltingat 234 to 235 C. (decomposition). When the crystals are poured into 10percent aqueous ammonia solution, crystals are free2-amino-7-nitro-5-phenyl-3H-1,4- benzodiazepine are obtained.Recrystallization from tetrahydrofuran yields yellow granules melting at227 to 228 C. (decomposition). Yield: 93 percent.

Elementary analysis:

Calculated for C, H, N O,

C: 64.27, H: 4.32, N: 19.91 Found: C: 64.48, H: 4.47, N: 19.77

EXAMPLE 27 Elementary analysis:

Calculated for C l-i ChN (C H clNflHCl) C: 53.87, H: 4.52, N: 11.79Found: C: 53.92, H: 4.88, N: 11.27

37 Parts of the oily substance prepared in Example 20(2-amino-5-methyl-a-phenylbenzylideneaminoacetonitrile) is dissolved in200 parts by volume of methanol. The solution is saturated with dryhydrogen chloride gas under ice cooling, followed by being left standingfor 1 hour. The solution is concentrated under reduced pressure to aboutone-third of the initial volume. The concentrate is poured into 700parts of a concentrated aqueous ammonia solution. The resultingprecipitates are collected by filtration, washed with water and driedover sodium sulfate. The procedure gives 2-amino-7-methyl-5-phenyl-3Hl,4- benzodiazepine as crystals, which are crystallized from ethanol togive 23.5 parts of pale yellow prisms melting at 222 to 223 C.(decomposition). Yield: 63 percent.

Elementary analysis:

Calculated for C H N C: 77.08, H: 6.06, N: 16.86 Found: C: 77.24, H:6.08, N: 16.67

EXAMPLE 29 A solution of 16.6 parts of the oily substance prepared inExample 21(2-amino-5-trifluoromethyl-aphenylbenzylideneaminoacetonitrile) in 60parts by volume of ethanol is saturated with dry hydrogen chloride gasunder ice cooling, whereby 2-amino-5- phenyl-7-trifluoromethyl-3H-l,4-benzodiazepine dihydrochloride is precipitated. The precipitates arecollected by filtration, washed with acetone and dried. The motherliquor is left standing for a while, whereby further crystals of thedihydrochloride are obtained. The above procedures give 13 parts intotal of the dihydrochloride. Melting point: 215 to 223 C.(decomposition).

The dihydrochloride obtained above is poured into 10 percent aqueousammonia solution with stirring. After 30 minutes, the precipitatedcrystals of 2-amino- -phenyl-7-trifluoromethyl-3H- l ,4-benzodiazepineare collected by filtration, washed with water and dried. The crystalsare recrystallized from a mixture of acetone and n-hexane to givecolorless flakes melting at 190 to 193 C. (brown at 180 C.). Yield: 9.7parts (58 percent).

Elementary analysis:

Calculated for c,,H,,F,N,

C: 63.36, H: 3.99, N: 13.86 Found: C: 63.25, H: 3.99, N: 13.79

EXAMPLE 30 A solution of parts of the oily substance prepared in Example22 (2-amino-S-methoxy-a-phenylbenzylideneaminoacetonitrile) in 50 partsof methanol is saturated with dry hydrogen chloride gas under icecooling, followed by being left standing at the same temperature for 1hour. The mixture is concentrated under reduced pressure to about onethird of the initial volume and the concentrate is poured into anaqueous solution of ammonia followed by extraction with chloroform. Thechloroform extract is washed with water and dried over sodium sulfate,followed by distillation of the chloroform under reduced pressure. Theprocedure yields 2-amino-7-methoxy-S-phenyl-3H-1 ,4- benzodiazepine asyellow crystals. The crystals are recrystallized from chloroform to givepale yellow necdles melting at 184 to 185 C. Yield: percent.

Elementary analysis:

Calculated for C H N O C: 72.43, H: 5.70, N: 15.84 72.47, H: 5.87, N:15.69

' Found: C:

What is claimed is: 1. A method for producing a compound of the formula:

wherein R has the same meaning as above and the respective benzene ringsA and B may have one or more substituents as defined above to a ringclosure in the presence of an acid or alkali.

'2. The method as claimed in claim 1 wherein R is alkyl.

3. A method according to claim 1 wherein the ring closure is conductedin the presence of an alkali metal hydroxide in an amount not lower thanabout 1 mole of alkali metal hydroxide per mole of nitrile in a solventselected from the group consisting of methanol, ethanol, propanol,butanol, acetic acid and propionic acid.

4. A method according to claim 1, wherein the ring closure is conductedin the presence of an alkali metal hydroxide in an amount not lower thanabout 1 mole of alkali metal hydroxide per mole of nitrile in a solventselected from the group consisting of methanol, ethanol, propanol,butanol, acetic acid and propionic acid.

5. A method according to claim 1, wherein the ring closure is conductedin the presence of a strong acid in an amount not lower than about 2moles of acid per mole of nitrile in a solvent selected from the groupconsisting of methanol, ethanol, propanol, butanol, acetic acid andpropionic acid.

6. A compound of the formula wherein R represents alkyl and cycloalkylof up to six carbon atoms and the respective benzene rings A and B mayhave one or more substituents which are the same or different andselected from the group consisting of halogen, nitro, trifluoromethyl,lower'alkyl and lower alkoxy.

2. The method as claimed in claim 1 wherein R1 is alkyl.
 3. A methodaccording to claim 1 wherein the ring closure is conducted in thepresence of an alkali metal hydroxide in an amount not lower than about1 mole of alkali metal hydroxide per mole of nitrile in a solventselected from the group consisting of methanol, ethanol, propanol,butanol, acetic acid and propionic acid.
 4. A method according to claim1, wherein the ring closure is conducted in the presence of an alkalimetal hydroxide in an amount not lower than about 1 mole of alkali metalhydroxide per mole of nitrile in a solvent selected from the groupconsisting of methanol, ethanol, propanol, butanol, acetic acid andpropionic acid.
 5. A method according to claim 1, wherein the ringclosure is conducted in the presence of a strong acid in an amount notlower than about 2 moles of acid per mole of nitrile in a solventselected From the group consisting of methanol, ethanol, propanol,butanol, acetic acid and propionic acid.
 6. A compound of the formula